Proximal spinal muscular atrophies (SMAs) are a group of inherited neuromuscular disorders characterized by the degeneration of spinal motorneurons leading to muscular paralysis with muscular atrophy. Spinal muscular atrophy (SMA) is the second most common autosomal recessive disease (behind cystic fibrosis), occurring in approximately 1 in 6,000 live births. In SMA, the anterior horn cells in the spinal cord die, resulting in progressive muscle weakess and ultimately, in some cases, in the inability to breathe and swallow.
Because SMA exists as a broad spectrum from very severe infantile to very mild chronic forms of the disease, SMA has been classified into three main clinical types. Type 1 SMN, the severe form of Werdnig-Hoffman disease, has an onset at birth or before 6 months and death of respiratory distress usually occurs within two years, and children will never be able to sit or walk due to profound muscular weakness. Type II SMA (intermediate form) patients can usually sit but cannot walk or stand unaided (see Werdnig, G. Psychiat, 1894, 26, 706-744; Hoffmann, J. Muenchen Med. Wschr. 1900, 47, 1649-1651). Type 1 ml SMA patients (Kugelberg-Welander disease) show the first clinical signs after 18 months, evolving to a chronic course (Kugelberg, E. and Welander, L. Arch. Neurol. Psychiat. 1956, 75, 500-509). For each of these types of SMA, there is no known cure; rather, therapy is limited to amelioration of the symptoms produced by this insidious disease.
The gene involved in the pathology of SMA is the SMN gene. One copy of the gene, SMN1, is closer to the telomere and produces full-length transcripts, resulting in full-length and functional SMN protein. The other copy of the gene SMN2, is a homologous copy (differing from SMN1 by only 5 nucleotides); however, SMN2 transcripts are alternatively spliced, resulting in mainly truncated transcripts lacking exon 7, although some full-length transcripts are also produced. In patients with SMA, the SMN1 gene is either deleted or has point mutations, and thus these patients have a deficiency of full-length SMN1 protein. The severity of the disease is also believed to depend on the SMN2 copy number in SMA patients, since SMN2 is actually capable of producing some full-length protein. Because SMN2 is capable of producing some full-length protein, it has been suggested that promoting the activity of SMN2 would lead to the production of additional functional full-length protein in motor neuron cells, thereby minimizing or eliminating the effects of SMA. For a discussion of the genetic basis, therapies, emerging research, and diagnostic aids for SMA see, www.fsma.org (Families of Spinal Muscular Atrophy); Nicole et al. Muscle & Nerve, 2002, 4-13; Lefebvre et al. Human Molecular Genetics 1998, 7, 1531-1536; Gavrilov et al. Nature Genetics, 1998, 20, 230-231; Monani et al., Human Molecular Genetics 2000, 9, 333-339; Hsieh-Li et al. Nature Genetics, 2000, 24, 66-70); and references cited therein.
Despite the knowledge gained about the genetic basis of the disease, there remains a substantial need to develop therapies for the treatment of Spinal Muscular Atrophy. Because patients affected by SMA still have a copy of the SMN2 gene, it would be desirable to develop promoters of the SNM2 gene that would ultimately lead to the production of additional full-length and functional SMN protein, thus minimizing or eliminating the effects of SMA caused by the deletion of the SMN1 gene.